Laboratory Experiment

pubs.acs.org/jchemeduc

Investigating a Chemoselective Grignard Reaction in an

Undergraduate Discovery Lab To Predict Reactivity and Final
Products
Michael J. Maher,*,† Colin O. Hayes,† Francesca A. Vaccaro,‡ Cailyn B. Flynn,‡ R. Paxton Thedford,†
and Clifton J. Stephenson*,‡
†
Department of Chemistry, The University of Texas at Austin, 105 East 24th Street, A5300, Austin, Texas 78712, United States
‡
Department of Chemistry, Loyola University New Orleans, 6363 Saint Charles Avenue, New Orleans, Louisiana 70118, United
States
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*
Downloaded via INDIAN INST OF TECH BOMBAY on February 28, 2022 at 04:25:25 (UTC).

S Supporting Information

ABSTRACT: A discovery-based Grignard experiment that emphasizes several

important concepts in organic chemistry is reported. The Grignard reagent from 1-
bromo-4-chlorobenzene was prepared and reacted with dimethylformamide (DMF) to
synthesize 4-chlorobenzaldehyde. Students were tasked with predicting halogen
reactivity in the formation of the Grignard reagent, predicting the final product, and
drawing a reasonable mechanism for the reaction with DMF. The Grignard reaction
with tertiary amides is typically not discussed in the organic chemistry curriculum, so
the students have an opportunity to apply concepts covered in lecture to a new
situation. Lastly, the students experimentally verified the identity of the product using
thin layer chromatography, melting point analysis, gas chromatography, IR and NMR
spectroscopy, and mass spectrometry.
KEYWORDS: Organic Chemistry, Grignard Reagents, Aldehydes/Ketones, Laboratory Instruction, Inquiry-Based/Discovery Learning,
Second-Year Undergraduate, Upper-Division Undergraduate

■ INTRODUCTION
The Grignard reaction is a fundamental tool in organic
Scheme 1. Preparation of the Grignard Reagent and
Subsequent Reaction with Dimethylformamidea
chemistry because it forms new carbon−carbon bonds and
introduces new functional groups. As a result, the Grignard
reaction is taught in all organic chemistry classes. In teaching
laboratories, students often prepare the Grignard reagent of
bromobenzene and react it with carbon dioxide or
benzophenone to yield benzoic acid or triphenylmethanol,
respectively.1 Over the years, the emphasis on discovery-based
pedagogy2 has resulted in the design of many new Grignard
experiments.3−5 However, until very recently, no attention has
been given to experiments where students prepare a Grignard
reagent selectively from the more reactive halogen in a
dihalogenated species.6 Furthermore, most Grignard exercises
result in the formation of highly predictable products such as
tertiary alcohols. To the best of the authors’ knowledge, there a
The organomagnesium bromide (2) forms selectively over the
are no published lab exercises that use less conventional organomagnesium chloride (4). The reaction with DMF produces an
electrophiles where the product is not obvious to the students. aldehyde after hydrolysis.
It was our goal to design a discovery-based experiment where
students apply concepts learned in lecture to both the
formation of the Grignard reagent and its subsequent reaction forms selectively over the organomagnesium chloride (4).
with an unknown electrophile. First, students prepared the Second, the students reacted the Grignard reagent with
Grignard reagent from 1-bromo-4-chlorobenzene (1, Scheme dimethylformamide (DMF) to synthesize 4-chlorobenzalde-
1). In the presence of two different aryl halogens, the more
reactive halogen will react with magnesium selectively.7−9 In Received: June 9, 2015
this case, since the Caryl−Br bond is weaker and more labile Revised: June 10, 2016
than the Caryl−Cl bond, the organomagnesium bromide (2) Published: June 28, 2016
© 2016 American Chemical Society and
Division of Chemical Education, Inc. 1464 DOI: 10.1021/acs.jchemed.5b00453
J. Chem. Educ. 2016, 93, 1464−1469
Journal of Chemical Education
hyde (3) and not 4-bromobenzaldehyde (5). This powerful
reaction is known as the Bouveault aldehyde synthesis,10 but it
is not usually covered in undergraduate lecture. The product of
the reaction is not obvious; however, the students can predict
the correct product and propose a mechanism leading to the
aldehyde. The students should recognize that the nucleophilic
Grignard reagent attacks the electrophilic carbonyl in DMF.
Upon formation of the Grignard reagent and addition to DMF,
the initial product is a hemiaminal salt, which cannot undergo
further reaction. Upon acidic workup, the hemiaminal
(analogous to a hemiacetal) decomposes to the aldehyde
(Scheme 2). The key is recognizing that the hemiaminal is
Scheme 2. Mechanism of the Reaction between a Grignard
Reagent and Dimethylformamide and Subsequent
Hydrolysis
unstable and is the same intermediate observed in imine
hydrolysis. In lab, the students can verify the identity of the
product using IR spectroscopy, melting point, mass spectrom-
etry (MS), gas chromatography (GC), and NMR spectroscopy.
This experiment has been performed by 10 undergraduates
at the University of Texas at Austin as part of a research class
and by 24 undergraduates over the past two years in the major’s
section of the Organic II Lab course at Loyola University New
Orleans, which meets twice a week for 3-h periods. The
experiment was performed over the course of four 3-h periods,
but can be easily tailored to be completed in two or three 3-h
lab slots. At Loyola, the students were presented an outline of
the experiment but were not told what the correct product
should be. The students were given a prelaboratory assignment
(Supporting Information) that guided them toward a better
understanding of the mechanism, which helped them predict
the correct product before entering the lab. The students
performed the experiment in pairs, and individual under-
standing was assessed based on a postlaboratory quiz
(Supporting Information).
■ PEDAGOGICAL SIGNIFICANCE
This lab focused on three main goals. The first goal was to help
students generate hypotheses about chemical reactivity in a
method that emphasizes generative learning. The students
should be capable of discerning the difference in reactivity of
the Caryl−Cl and the Caryl−Br bond in the formation of the
Grignard reagent. However, because the students have never
been exposed to the reaction of a Grignard reagent with tertiary
1465
Laboratory Experiment
amides, the students needed to develop their own answers. The
second goal was to teach new laboratory techniques such as
column chromatography. The third goal was to have the
students demonstrate mastery of a new concept by character-
izing their product and reflecting on how their predications
aligned with experimental results.
■ EXPERIMENTAL OVERVIEW
A detailed experimental procedure, list of chemicals, and
instrumentation can be found in the Supporting Information
(See Instructor Notes).
Lab Period 1
Students synthesized 3. The Grignard reagent from 1 equiv of
magnesium and 1 equiv of 1 was prepared in refluxing diethyl
ether. After 1 h of refluxing, the Grignard reagent (2) was
cooled to 0 °C in an ice bath and DMF was slowly added. After
stirring for 20 min, the solution was acidified with 1 N HCl.
The product was extracted with diethyl ether, and the crude
product was obtained by evaporation of the solvent using a
gentle stream of nitrogen.
Lab Periods 2 and 3
Students were given a lecture about thin layer chromatography
(TLC) and flash chromatography. Then, the students
performed TLC and compared the Rf value of the crude
product and starting material using several different TLC
conditions. Selective stains for aldehydes (2,4-dinitrophenylhy-
drazine, DNP) were introduced and used to stain the TLC
plates. Then flash chromatography using silica gel as the
stationary phase and 7% diethyl ether in hexanes as the mobile
phase was performed in groups of two. Students collected
approximately 10−20 15 mL fractions. TLC was used to
determine which fractions contained the product. Rotary
evaporation was used to remove the solvent to yield purified
product.
Lab Period 4
Students collected characterization data, including IR and NMR
spectroscopy, melting point, GC, and MS.
■
SAFETY HAZARDS
Splash-proof goggles, gloves, and lab coats should be worn
during the lab. All reactions should be performed in a properly
functioning fume hood. All organic solvents used within this lab
are flammable and irritants. Hexanes contain n-hexane, which is
a known neurotoxin and should be handled with special care.
Diethyl ether is prone to form explosive peroxides, and only
fresh and anhydrous diethyl ether should be used. The reaction
with DMF is highly exothermic. DMF should be added
dropwise to the cooled solution of Grignard reagent. Flash
chromatography uses pressurized columns (∼2−4 psi), and a
vent should be used to relieve excess pressure. Students should
assume that the product is an irritant and toxic. Additional
safety data may be found in the SDS for each compound.
■ RESULTS AND DISCUSSION
Students were assigned a prelaboratory exercise for which about
half predicted that the C−Br bond of 1 would react
preferentially, with most basing their prediction on the better
leaving group ability of bromide over chloride in nucleophilic
substitution reactions. However, the better leaving group
argument may not be the best explanation for the Grignard
reaction because the Grignard reagent formation is suggested to
DOI: 10.1021/acs.jchemed.5b00453
J. Chem. Educ. 2016, 93, 1464−1469
Journal of Chemical Education Laboratory Experiment

occur via single electron transfer or halogen abstraction.11 In

most undergraduate organic classes, the mechanism for the
formation of Grignard reagents is not discussed, and this
laboratory exercise presented a prime opportunity to discuss
these concepts with the students. After completion of the lab,
the reactivity was explained to the students in terms of bond
dissociation energies. In this experiment, the Caryl−Br bond is
weaker than the Caryl−Cl bond by approximately 13 kcal/mol,
which makes it more labile in the reaction.12 At 308 K, this
difference in bond dissociation energies corresponds to a
selectivity of 109:1, which could explain why 2 forms much
faster than 4.
As part of the prelaboratory exercises, the students were
required to draw the mechanism for an acid catalyzed
hydrolysis of an acetal. Then, the students were asked to
draw the mechanism for the reaction between a Grignard
reagent and DMF and the subsequent hydrolysis. About one-
third of the students were able to correctly predict the product Figure 1. Gas chromatography data of the product and potential
and draw an acceptable mechanism. A majority of students products. Suggested separation conditions are listed in the Supporting
stopped at the hemiaminal and did not recognize that Information.
hemiaminals hydrolyze analogously to hemiacetals. At this
point, showing the students the correct product before data for the melting points are shown in Table 1. As shown, the
revealing the whole mechanism gave them another opportunity melting point of the product nearly matches that of 3.
to work through the mechanism. The full mechanism was
discussed later, after students turned in drafts of their formal lab Table 1. Melting Point Data
reports.
Overall, the experiment was successful. Around 75% of the Molecule Melting Point (Lit. Value),a °C
student groups successfully formed the Grignard reagent. The 1-Bromo-4-chlorobenzene (1) 67−69 (68)
remainder of the groups were instructed to start the experiment 4-Bromobenzaldehyde (5) 59−60 (58)
over. After the second attempt, all groups were able to form the 4-Chlorobenzaldehyde (3) 46−49 (47)
Grignard reagent and isolate a product. In many cases, the Product of reaction Crude: 43−45
crude product was isolated as a waxy solid, which is normal Post column: 47−49
a
because the melting point of the product is relatively close to See ref 14.
room temperature. The authors have demonstrated that the
crude product is typically more than 90% pure and further The students also characterized their products using IR
purification is not necessary for characterization and (Figure S1) and NMR spectroscopy (Figure 2). In the IR
completion of the laboratory exercise. However, column spectra, the fingerprint region can be used to distinguish 3 and
chromatography was used at Loyola to teach a new purification 5. Typically, carbon−halogen bonds absorb below 1000 cm−1.15
technique. First, the students were taught how to use TLC to However, the Caryl−halogen stretch absorbs at 1000−1100
determine separation conditions. In most cases, the students’ cm−1.16 In the IR spectra shown in Figure S1, the Caryl−Cl
TLC plates showed one or two spots. After staining with a
solution of DNP, the major spot turned red-orange, which
suggests the presence of an aldehyde.13 The students were
taught that aldehydes and ketones react with DNP to form a
hydrazone, which caused the aldehyde spot to turn color on the
TLC plate. Then, the students collected fractions by eluting
their product through a silica column using 7% ether in hexanes
as the eluent. TLC was used to confirm which fractions
contained the desired product, and rotary evaporation of the
solvent resulted in a white solid. Crude yields ranged between
50 and 80%. However, the yields dropped to around 15−30%
after purification by chromatography. Although the percent
yields were low, each group had enough material to fully
characterize their product.
The purity and identity of the product can be determined by
a variety of chromatographic methods, including GC. Figure 1
shows the GC of the starting material (1), potential products
(3, 5), and product from the reaction. The retention time of the
product matches the retention time of 3. Additionally, a
mixture of the experimental product and 3 showed one peak, Figure 2. NMR spectra in CDCl3 of the starting material, potential
further supporting that the product is 3 as predicted. Students products, and the product of the Grignard reaction. The spectra have
then measured the melting point of their product and been referenced to the solvent residual peak (7.26 ppm), which has
compared it to the melting points of 1, 3, and 5. Representative been removed for clarity.

1466 DOI: 10.1021/acs.jchemed.5b00453

J. Chem. Educ. 2016, 93, 1464−1469
Journal of Chemical Education
Figure 3. Mass spectrometry data using electron ionization.
bond is present at 1080 cm−1. The Caryl−Br bond in 5, being
weaker, absorbs at a lower frequency (1065 cm−1) and is not
observed in the product. Figure 2 shows the 1H NMR spectra
of the starting material, the two potential products, and the
product from the experiment. The singlet near 10 ppm is
characteristic of an aldehydic proton. The product can be
referenced to the known spectra of 3 and 5. The aldehydic
proton in 3 is slightly downfield relative to 5.
The IR and 1H NMR spectra, without reference to literature
spectra, would not be able to distinguish 3 and 5. However, the
identity of the product can be fully verified by MS using
electron ionization. Figure 3 shows the spectra of the 1, 3, 5,
and the experimental product. It is clear from the molecular ion
peaks alone that the product is 3 and not 5. The MS data can
be used as an additional exercise to complement what the
students have learned in lecture. For example, both 3 and 5
have M + 2 peaks because of the halogen isotopes. However,
using the relative abundance of each peak, it is clear that the
product has 1 Cl and 0 Br atoms. Additionally, the base peak is
1467
Laboratory Experiment
the M − 1, which is the MS signature of the aldehyde
functional group. The key fragments are listed in Table 2.
Attempting to assign each fragment is an excellent exercise for
the students.
This experiment worked very well at Loyola. The Loyola
students were all able to synthesize, isolate, and purify 3. This
experiment was taught as part of an advanced synthesis and
characterization lab for second-year chemistry majors. As such,
students were expected to use and apply their knowledge from
previous experiments while learning advanced synthesis,
characterization, and purification techniques. This experiment
allows students to draw on knowledge learned in class and
apply it to a reaction that was not directly addressed during
lecture. Additionally, a major focus of this experiment was
training students to use modern instrumentation to characterize
their product. The use of flash chromatography, IR and NMR
spectroscopy, and MS allows students to observe the power of
modern purification and characterization techniques.
DOI: 10.1021/acs.jchemed.5b00453
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Journal of Chemical Education Laboratory Experiment

Table 2. List of Relevant Mass Spectrometry Fragments This experiment would be a strong addition to an
introductory organic chemistry class or an upper level synthesis
Molecule Peak m/z
lab class depending on how each instructor tailors it. This
1-Bromo-4-chlorobenzene (1) [M]+ 190 experiment combines hypothesis-driven discovery with charac-
[M + 2]+ 192 terization techniques to help support a predicted mechanism/
[M + 4]+ 194 product. This experiment also provides instructors a versatile
[Chlorophenyl]+ 111 platform for teaching pedagogy related to mechanistic under-
[Chlorophenyl + 2]+ 113 standing of reactions, synthetic techniques, and advanced
4-Bromobenzaldehyde (5) [M]+ − 1 183 characterization techniques.

■
[M]+ 184
[M + 2]+ − 1 185 ASSOCIATED CONTENT
[M + 2]+
[Bromophenyl]+
186
155
*
S Supporting Information

[Bromophenyl + 2]+ 157 The Supporting Information is available on the ACS

4-Chlorobenzaldehyde (3) [M]+ − 1 139 Publications website at DOI: 10.1021/acs.jchemed.5b00453.
[M]+ 140 Student handout, prelaboratory exercise, postlaboratory
[M + 2]+ − 1 141 quiz, list of chemicals, instructor notes, and Figure S1
[M + 2]+ − 1 142 (PDF, DOCX)

[Chlorophenyl]+ 111
[Chlorophenyl + 2]+ 113
At Loyola, the students were assessed with a postlab quiz
(average score ∼75%), which was compared to the results of
the prelaboratory assignment (average score ∼60%). In the
mechanism problem (Question 1, Supporting Information),
about 75% of the students were able to correctly show the
addition of the Grignard reaction with DMF. About 50% of the
students were able to successfully draw the hydrolysis of the
hemiaminal to the aldehyde. Around half of the students were
also able to predict the product of a Grignard reaction with a
different tertiary amide (N,N-dimethylbenzamide), which
results in ketone. A majority of the students seemed to
demonstrate mastery of reaction as demonstrated by their
writing in their lab reports.
Beyond what was done at Loyola, this experiment has the
potential to be pedagogically versatile. At Loyola, this
experiment was covered over a two-week period (four 3-h
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail: mmaher13@utexas.edu.
*E-mail: cjs@loyno.edu.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
The authors thank the undergraduates who participated in the
testing of this experiment. M.J.M. thanks Katie Hurley for a
detailed reading of the manuscript and thoughtful suggestions.
M.J.M. thanks the National Science Foundation Graduate
Research Fellowship (Grant No. DGE-1110007) for financial
support. Any opinion, findings, and conclusions or recom-
mendations expressed in this material are those of the authors
and do not necessarily reflect the views of the National Science
Foundation or the sponsors.

laboratories). It is the authors’ opinion that the time can be
reduced to two 3-h lab periods if no purification technique is
used. Another benefit of this experiment is that the aldehyde
can also be used for a subsequent reaction in a multistep
synthesis. For example, the students at Loyola carried out a
Wittig reaction (not reported here) with 3 to synthesize (E)-1-
chloro-4-styrylbenzene. Overall, each instructor can tailor this
reaction to focus on the concepts he or she feels need
additional emphasis. For example, this experiment combines
the topics of bond strengths, Grignard formation, nucleophilic
addition, hydrolysis, and important characterization techniques.
The authors believe that the students have learned to think
more clearly about chemical reactivity and learned how to
support/refute their hypotheses.
■
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CONCLUSIONS
A new Grignard experiment was employed that challenges
students on many fronts. In this experiment, the students
synthesized 4-chlorobenzaldehyde from the reaction of DMF
with the Grignard reagent from 1-bromo-4-chlorobenzene.
First, the students decided which Grignard reagent forms given
an option of two. Second, the Grignard reaction with DMF is
one that is not covered in lecture, which allowed the students to
apply concepts learned in class to a new situation. Lastly,
students characterized their products using common laboratory
techniques.
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J. Chem. Educ. 2016, 93, 1464−1469